1 Rheumatology Unit and Cardiovascular Research Laboratory, First Department of Propaedeutic and Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

2 Department of Nutrition and Dietetics, Group of Biostatistics, Epidemiology and Research Methods, Harokopio, University, Athens, Greece

3 First Department of Cardiology, Ippokrateion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

4 The Dudley Group NHS Foundation Trust, Dudley, and Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK

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Abstract

Introduction

Rheumatoid arthritis (RA) is associated with a high cardiovascular disease (CVD) risk,
whereas arterial hypertension is a major modifiable CVD risk factor with still unclear
prevalence in RA disease. We conducted a comprehensive study on hypertension characteristics
evaluating for the first time out-of-office blood pressure (BP) in a typical contemporary
RA cohort.

Methods

Assessment of office and out-of-office BP (when office systolic/diastolic BP was >129/79)
and vascular studies including evaluation of aortic stiffness, carotid hypertrophy/plaques
and ankle-brachial index, were performed in 214 consecutive, consenting RA patients
free of CVD (aged 58.4 ± 12.3 years, 82% women). As comparators regarding office hypertension
measurements, data from 214 subjects (1:1 matched for age and gender with the RA patients)
derived from a cohort designed to assess the prevalence of hypertension in the general
population were used.

Results

The prevalence of declared known hypertension in the RA population was 44%. Of the
remaining RA patients, 2 in every 5 individuals had abnormal office BP (systolic/diastolic
>139/89 mmHg), contributing to almost double the prevalence of declared/office hypertension
compared to the general matched population (67% vs. 34%). Out-of-office (home or ambulatory
24 hour) BP measurements revealed that: (i) a 54% prevalence of actual hypertension
in RA, in other words almost 10% of the patients were unaware of having hypertension
and (ii) 29% of the RA patients with known hypertension were not well controlled.
Actual hypertension was positively associated with age and body mass index, and inversely
with the use of biologic drugs. Overall, almost 1 out of 5 presented the 'white coat’
phenomenon. An intermediately compromised vascular phenotype was evident in this “white
coat” subgroup (lying between patients with sustained normotension and sustained hypertension)
in terms of aortic stiffness, carotid hypertrophy and ankle-brachial index, even after
adjustment for confounders.

Conclusion

Beyond any doubt on the basis of out-of-office evaluation, arterial hypertension in
RA has a high prevalence, low awareness and poor control, as well as substantial and
vascular damage-associated “white coat” phenomenon. Thus, correct diagnosis and effective
treatment of hypertension is of key importance in RA for CVD risk reduction.

Introduction

Compared to the general population, patients with rheumatoid arthritis (RA) have almost
twice the risk of developing cardiovascular disease (CVD)
[1] and their risk for myocardial infarction corresponds to that of non-RA patients who
are 10 years older
[2]. CVD mortality accounts for almost half of all-cause mortality in RA
[3,4]. This is thought to be mediated by accelerated atherosclerosis
[5,6] and subclinical vasculitis
[7,8]. The increased burden of established CVD risk factors in RA patients
[9] explains only partly the excess CVD mortality
[10], suggesting that systemic inflammation participates in the development of CVD.

Arterial hypertension is a major modifiable CVD risk factor worldwide
[11]. Previous studies suggest that the prevalence of hypertension is increased in RA
[12,13], possibly related to clinical status
[14] and the related physical inactivity
[15] as well as to genetic factors
[16,17]. As recently reviewed, however, the evidence is still conflicting
[18]. This is in part due to the fact that the existing data are based on single-visit
office blood pressure (BP) readings, whereas data based on out-of-office BP evaluation
(which provides the gold-standard assessment of BP-associated CVD risk
[19]) are lacking. As a result, data on white coat hypertension (WCH) and masked hypertension
(MH) phenomena, two BP phenotypes associated with potentially intermediate CVD risk
[19], are also lacking in RA patients.

Elevated BP in RA may derive from increased oxidative stress and systemic inflammation,
impaired endothelial function, vasoconstriction and increased total peripheral resistance,
as well as arterial stiffening
[5,9,12,13]. RA-related drugs, such as corticosteroids and nonsteroidal anti-inflammatory drugs,
and particular genetic polymorphisms, together with environmental factors, may also
precipitate BP elevation in RA
[12,13,16,17]. In contrast, anti–tumor necrosis factor and anti–interleukin 6 biologics appear
to have beneficial effects on endothelial function and arterial stiffness
[20,21] and thus may reduce BP independently of Disease Activity Score
[14].

In a contemporary cohort of consecutive RA patients free of established CVD, we evaluated
BP and assessed vascular organ damage. Our principal hypotheses were (1) that the
prevalence of hypertension in RA is higher than that in the general population and
(2) that specific BP diagnostic phenotypes, such as WCH and MH phenomena, have different
clinical significance in terms of vascular damage in RA patients. The following were
our specific aims: (1) to compare the prevalence of abnormal office BP measurements
to those observed in a 1:1 age- and gender-matched general population group free of
CVD, (2) to assess the actual prevalence of hypertension in RA by applying, for the
first time, out-of-office BP measurements to identify the awareness and effectiveness
of BP control as well as the prevalence of resistant hypertension, (3) to identify
factors associated with the presence of hypertension in RA and (4) to identify specific
BP diagnostic phenotypes, such as WCH and MH phenomena, and their association with
the extent of vascular damage.

Methods

The present study was approved by the Ethical/Scientific Committee of the “Laikon”
Hospital, and all participants provided their informed consent to participate according
to the Declaration of Helsinki.

Rheumatoid arthritis patients

From September 2010 until September 2012, 242 consenting, consecutive patients (mean
age 59.2 ± 12.3 years, 195 women (81%)) attending the outpatient Rheumatology Clinic
and meeting the American College of Rheumatology classification criteria
[22] were examined at the Cardiovascular Research Laboratory for global CVD risk stratification.
Ninety-five percent of them were inhabitants of the Attica province of Greece (which
includes 78% urban and 22% rural areas – mainly the city of Athens and its suburbs).
All patients underwent a medical interview and examination so that we could record
all the known classical CVD risk factors and drug treatments as well as the presence
of CVD. All biochemical data were retrieved from the patient’s records at the outpatient
Rheumatology Clinic of the department. The estimated creatinine clearance (eCCL) was
assessed by using the Cockcroft-Gault formula. Two hundred fourteen RA patients were
included in the present analysis (mean age 58.4 ± 12.3 years, 176 women (82%)) after
excluding 18 patients with established CVD, 2 with estimated creatinine clearance
less than 30 ml/min (due to the possibility of secondary hypertension) and 8 patients
without available office BP recordings.

Control group

RA patients were matched 1:1 by age and sex with 214 individuals randomly derived
from the ATTICA study database
[23]. In brief, the ATTICA study is a general population-based health and nutrition survey
that was conducted from May 2001 to December 2002 in the province of Attica, Greece.
The original sample included 3,042 participants, and the data selection was performed
among 2,285 (1,128 men) who were free of CVD or inflammatory disease.

Protocols for arterial blood pressure and hypertension assessment

BP in RA patients was measured in the morning (8:30 AM to 12:30 PM) during the vascular
tests after at least ten minutes of rest in the supine position under controlled room
temperature (22°C to 25°C). Triple BP recording was performed (with one-minute intervals
between readings) using the right arm and a previously validated automated oscillometric
device (WatchBP Office; Microlife AG, Widnau, Switzerland)
[24]. The average of the three BP readings was calculated and used in the subsequent analysis.

All participants with office systolic (S)BP/diastolic (D)BP 129/79 mmHg or lower were
considered to have optimal office BP and thus to have low probability of exhibiting
the MH phenomenon, since this is particularly observed in individuals with high normal
office BP
[25]. All others were advised to perform out-of-office BP measurements (either home BP
monitoring (HBPM) or 24-hour ambulatory BP monitoring (ABPM) according to their own
preference). These two methodologies are equally recommended by the European Hypertension
Society (ESH) 2007 guidelines
[19] for the detection of the WCH and MH phenomena. HBPM was performed with a previously
validated automated oscillometric device (WatchBP Home, Microlife AG)
[26] according to the ESH suggested protocol (seven-day BP recordings)
[27]. All patients underwent a brief tutorial about how to use the BP device correctly
and how to comply with the ESH recommendations for HBPM
[27]. The HBPM data were downloaded and analyzed using specifically designed software
(TRITON software package; Proton Labs, Athens, Greece) according to the built-in ESH
recommendations
[27]. ABPM measurements were performed according to the ESH 2007 guidelines
[19] using a previously validated automated oscillometric device (90207 ambulatory blood
pressure monitor; Spacelabs Healthcare, Snoqualmie, WA, USA)
[28]. All patients were advised to perform their regular activities during ABPM.

Overall, 93 of the 214 RA patients had optimal office BP readings. The data provided
in the results were calculated with the assumption that RA patients with optimal office
BP would have normal out-of-office BP. From among the remaining patients, 24 underwent
24-hour ABPM and 58 underwent HBPM, whereas 39 RA patients did not consent to undergo
out-of-office BP assessment. Figure
1 summarizes the protocol’s flow on the basis of BP assessment methodology. These 39
patients had characteristics similar to those of the overall cohort (mean age, 62.1
± 12.1 years; 82% women; mean body mass index, 28.9 ± 6.2 kg/m2; abnormal office BP, 36 patients; high normal BP, 3 patients; and hypertensives under
antihypertensive drug treatment, 14) and were excluded from the analysis regarding
the prevalance of WCH and MH phenomena, as well as regarding the prevalence of out-of-office
hypertension (unless already under drug treatment; n = 14). This fact may not have led to important underestimation of the MH phenomenon,
because only three of the thirty-nine patients had high normal office BP (Figure
1).

All the definitions of the hypertension phenotypes which have been applied were based
on the ESH guidelines and are summarized in Table
1[19,27].

Table 1.Definitions of hypertension phenotypes according to the European Society of Hypertension
recommendationsa

With regard to the control subjects, BP was measured at the end of the physical examination
in participants’ workplaces or at their homes while they were in the sitting position
and had been at rest for at least 30 minutes
[29]. BP recordings were performed by a cardiologist three times at the right arm, which
was relaxed at a 45° angle from the trunk and well-supported by a table (ELKA aneroid
sphygmomanometer; Von Schlieben Co, Munich, Germany). The SBP level was determined
by the first perception of sound (of tapping quality). The DBP was determined by phase
V, when the repetitive sounds become fully muffled (that is, disappear). The same
criteria used for RA patients were applied for BP classification.

Vascular studies

Vascular organ damage assessment included the investigation of aortic stiffness (carotid
to femoral pulse wave velocity (PWV)), common carotid hypertrophy (cross-sectional
area (CSA)) and carotid atheromatosis (carotid plaques) as previously described in
detail
[5]. The Ankle-Brachial Index (ABI) was assessed using a validated oscillometric automated
device (WatchBP Office ABI; Microlife AG)
[30]. All the vascular measurements were performed by the same experienced and dedicated
technician (GD Konstantonis) after BP recording. All participants were advised to
abstain from any vasoactive drug or substance (including BP-lowering drugs) on the
morning of the vascular examination.

Statistical analysis

Variables were tested for normality by the Kolmogorov-Smirnov test. Paired t-test, χ2 and Wilcoxon test were applied for comparison of the 1:1 matched RA and control populations
as appropriate. Binary logistic regression analysis was applied to find the independent
predictors of hypertension and BP control. The classical determinants, namely, age,
body mass index and sex traits, were constantly used in all models to further identify
RA-related and non-RA-related parameters which were associated with the dependent
variables. Regression analysis, analysis of variance and analysis of covariance (to
adjust for potential confounders) were applied to detect differences between diagnostic
BP phenotypes. Significance was defined as P < 0.05 throughout. Statistical analysis was performed using SPSS version 19.0 software
(SPSS Inc, Chicago, IL, USA). The results are presented as means ± SD or percentages,
and non–normally distributed continuous variables are presented as median values (50th
quartile) with interquartile ranges (25th to 75th quartiles) as appropriate.

Results

Prevalence, awareness and control of hypertension in rheumatoid arthritis

The prevalence of known hypertension was 44% in the RA cohort. Of the remaining RA
patients, almost two of every five had abnormal office BP measurements, reaching an
overall rate of 67% (males: 74%, females: 66%) of office BP-defined hypertension (Figure
2). This ratio was almost double that found in the 1:1 age- and gender-matched control
group (34%; males: 37%, females: 33%). RA patients had no statistically significant
differences in hypercholesterolemia, diabetes mellitus, current smoking and body mass
index compared to the control group from the ATTICA study (Table
2). Interestingly, although matched for age and gender, women with RA had a higher
prevalence of menopause than women in the control group. RA patients had higher C-reactive
protein levels than the controls (Table
2).

Figure 2.Prevalence of blood pressure levels under the studied conditions. Bar graph shows the prevalence in percent of known, office and actual blood pressure
(BP) on the basis of out-of-office BP assessment, either seven-day home BP monitoring
or twenty-four-hour ambulatory BP monitoring, in the overall rheumatoid arthritis
cohort as well as in the general population of the ATTICA study.

Table 2.Demographics of the 214 patients with rheumatoid arthritis and the 1:1 age- and gender-matched
control groupa

Out-of-office BP assessment (either seven-day HBPM or twenty-four-hour ABPM) revealed
that the actual prevalence of hypertension in RA was 54% (males: 55%; females: 54%).
As a consequence, approximately an additional 10% of the overall population were unaware
that they had hypertension (Figure
2). Moreover, 29% of the RA patients with known hypertension had uncontrolled out-of-office
BP. Overall, about one of every two RA patients (52%) with known hypertension had
abnormal out-of-office BP despite antihypertensive treatment.

Among the hypertensive RA patients, the prevalence of resistant hypertension (defined
as uncontrolled BP in the presence of at least three antihypertensive drugs, including
a diuretic) was 9% on the basis of office BP measurements or 5% on the basis of out-of-office
BP readings.

Less than 1% of the RA population exhibited the MH phenomenon. On the contrary, of
all RA patients, almost one (21%) of every five exhibited the WCH phenomenon; that
is, 29% of those treated for hypertension (Figure
3a) and 19% of those not treated for hypertension (Figure
3b) had WCH. Interestingly, these patients, regardless of the presence or not of antihypertensive
treatment (data not shown), presented an intermediately compromised vascular phenotype
as assessed by well-established biomarkers of arterial damage (Table
3). As shown in Table
3, WCH was associated with compromised aortic stiffness (PWV), common carotid hypertrophy
(CSA), carotid plaques and ABI, all biomarkers which are related to CVD mortality
in both hypertension and RA, at levels between sustained normotension and sustained
hypertension, although out-of-office BP levels were comparable between the WCH and
sustained normotension groups. Because significant differences in age, body mass index
and smoking were found between the three groups (Table
2), we performed further adjustment for potential confounders (including age, gender,
body mass index, smoking and mean BP) and found that the differences regarding PWV,
right CSA and right ABI persisted between the three groups (Table
2).

Discussion

This is the first detailed study of the prevalence and characteristics of hypertension
in RA patients without established CVD. It included age- and sex-matched non-CVD controls
from the same geographical area and race; it utilized assessment of both office and
out-of-office BP, thus enabling estimation of the actual prevalence of hypertension
in RA, as well as of the WCH and MH phenomena, which are important in terms of awareness
and inadequate therapy; and it incorporated assessment of vascular damage, allowing
the exploration of its associations with specific hypertension phenotypes.

The novel important findings of our present study, based on out-of-office BP, are
as follows. (1) The prevalence of hypertension in RA was clearly elevated (54%) compared
to that in the general population (34%), and it would have been even higher if out-of-office
BP assessment were available in the ATTICA study. (2) About 10% of the overall RA
cohort (or one of every four RA patients with confirmed hypertension) were not aware
that they had hypertension. (3) One of every two patients in the overall RA population
(or one in every three RA patients with confirmed hypertension) had uncontrolled BP.
(4) The prevalence of the MH phenomenon was negligible. (5) The WCH phenomenon was
observed in almost one of every five RA patients overall, which should be regarded
as an intermediate to high CVD risk BP phenotype in patients with RA because of the
presence of accelerated atherosclerosis, thus raising questions about the optimal
BP treatment strategy in this population. (6) We verified that particular RA treatment
modalities, but not inflammation per se, are significantly associated with the presence of hypertension and interfere with
BP control in addition to classical factors such as age and body mass index.

The observed high prevalence of hypertension (67%) on the basis of office BP is in
accordance with previously reported data from studies in which similar office BP measurements
were taken (70% in a population with a mean age 63 years
[12] and 57% in a population with a mean age of 59 years
[13]). Most importantly, even the actual prevalence of hypertension in RA on the basis
of out-of-office BP assessment was 1.6 times that in the ATTICA study. The data derived
from the ATTICA study were based on single-visit BP recordings (at the participants’
workplaces or homes) and are in general agreement with those reported in other studies
in the Greek population, which were based on office BP readings
[31-35]. It is thus expected that the prevalence of hypertension in the ATTICA study would
be lower if based on out-of-office BP methods (either HBPM or ABPM).

A major aim of the present study was to compare the prevalence of hypertension in
a typical contemporary cohort of RA patients to the prevalence of hypertension in
the general population. Therefore, among all the relevant previously published Greek
studies, we decided to use the most contemporary one in the general population and
the one which was carried out in exactly the same region as the RA cohort (Attica,
Athens). The ATTICA study was performed almost 10 years before the time the data from
the present RA cohort were gathered and thus may not depict the updated prevalence
of hypertension in the current general population, but the results are in line with
all other epidemiological studies published before or since
[31-35]. The fact that the precise method of BP measurement differed between the RA and non-RA
cohorts may have influenced the results. However, we believe that the magnitude of
the difference (twofold) observed in the prevalence of office hypertension between
the RA and general populations in this study is extremely unlikely to be due to these
limitations. As such, we suggest that the evidence for a higher prevalence of hypertension
in RA compared to the general population can be considered conclusive.

The reason for the increased prevalence of hypertension in RA is not clear. In the
present study, and in agreement with two previous studies
[12,13], a direct association between the prevalence of hypertension and inflammation (as
assessed by C-reactive protein) was not identified. However, we cannot exclude that
systemic inflammation plays a role in the development of hypertension in RA, because
(1) RA inflammation fluctuates, and this cross-sectional marker may not capture the
long-term cumulative inflammatory burden, and (2) the studied population was well-controlled
with conventional and biologic drugs, which affect C-reactive protein, endothelial
function, arterial stiffness and BP levels
[14,20,21]. Moreover, in the present study, the prevalence of menopause was increased by 15%
in RA compared with the matched general female population and was independently associated
with office hypertension. Given the fact that early menopause has been associated
with increased prevalence of hypertension
[36], as well as with the incidence of RA
[37], these findings may represent a pathogenic link between hypertension and RA. However,
biologic drugs exert a beneficial effect on endothelial function and arterial stiffness
[20,21] and thus may prevent the incidence of hypertension
[14].

The need to improve the awareness of hypertension among hypertensive RA patients is
highlighted by the present study, in which the actual percentage of unawareness was
23% based on out-of-office BP measurements. Data based on out-of-office BP measurement
are lacking in large general population groups. For purposes of comparison, we report
herein the corresponding data from the present RA cohort on the basis of office BP
measurements. Using these measurements, 46% of RA patients with hypertension were
not aware that they had it, whereas the published data from the ATTICA study in a
similar age group (55 to 65 years old) were about 40%
[35]. In a previous study, about 35% of a RA cohort in the same age group (55 to 65 years
old) who were unaware of their hypertension
[12].

Moreover, the present data emphasize the need to improve the effectiveness of BP treatment
in RA because 29% (on the basis of out-of-office BP) or 35% (on the basis of office
BP) of those who were aware of having hypertension had uncontrolled BP. The published
data from the ATTICA study in a similar age group (55 to 65 years old) were about
34%
[35]. In a previous RA cohort in the same age group (55 to 65 years old), this figure
was about 55%
[12]. Physicians taking care of RA patients should optimize treatment control by taking
into consideration the fact that leflunomide, as shown in the present study and as
previously described
[38], restricts effective BP control. Although the underlying mechanism is not clear,
it is suggested that it might be mediated by the activation of the sympathetic nervous
system
[38]. Previous studies
[12,13] have not provided consistent results regarding other RA-related drugs (for example,
corticosteroids, nonsteroidal anti-inflammatory drugs). Similarly, in the present
study, we did not identify the well-described effect of corticosteroids
[39] and nonsteroidal anti-inflammatory drugs on BP. This is most probably related to
treatment preferences that prevail in each cohort. In the present study, only 5% of
patients were being treated with nonsteroidal anti-inflammatory drugs and only low-dose
corticosteroids (less than 5 to 7 mg/day) were used. The latter may have undetectable
effects on BP level as previously discussed
[12]; however, their effects may be deleterious for the arteries in the long run, and
thus their use should be carefully considered
[40]. Notably, in the present study, body mass index was associated with the presence
of hypertension as previously observed
[12,13], as well as with poor BP control. Therefore, the described paradoxical association
of obesity with decreased CVD in RA patients
[9] seems to be mediated by other pathways that counterbalance the effect of obesity
on BP.

Data regarding the prevalence of resistant hypertension in RA are lacking so far.
In this cohort, the prevalence was found to be relatively high (9% in RA vs. 5% in
the general population as published in the literature on the basis of office BP readings)
[41]. However, this issue needs further thorough investigation because significant differences
exist regarding the prevalence of resistant hypertension from population to population
[41]. Further research is also needed to elucidate whether poor BP control in RA is due
to the well-described worldwide physician’s inertia
[42,43] or whether RA-specific peculiarities, such as treatment modalities, increase the
prevalence of resistant hypertension and/or the presence of increased aortic stiffness
[5,44], also contribute.

The optimal BP diagnostic method and the goals of treatment are unresolved issues
in hypertension research
[19]. The results of our present study suggest that there are peculiarities in the RA
population because of the negligible prevalence of MH (less than 1% vs. the anticipated
10% to 15% in the general population
[19]), whereas the prevalence of the WCH phenomenon was relatively high (21% vs. the anticipated
15% in the general population
[19]). High prevalence of the WCH phenomenon has also been described in diabetes mellitus
type 2
[45], which shares common characteristics with RA
[5], including increased arterial stiffness, which may partly contribute to the WCH phenomenon.
The current hypertension guidelines advise clinicians not to treat individuals who
exhibit the WCH phenomenon unless there is evidence of target organ damage
[19]. In the present cohort, RA patients with the WCH phenomenon (treated or not treated
for hypertension) presented with substantial vascular damage. The prevalence of carotid
plaques was 60%, and we observed an intermediate level of carotid hypertrophy, aortic
stiffness and reduced ABI compared to those RA patients with sustained normotension
and sustained hypertension. These findings are in line with previous findings in non-RA
populations
[19]. We suggest that, in similar cases, the decision regarding office BP reduction in
RA patients by either drug treatment titration (in those already receiving antihypertensive
drugs) or drug treatment initiation (in those currently untreated with drugs) should
be carefully weighed on the basis of patient age, the degree of vascular damage, the
presence of orthostatic hypotension and, certainly, the out-of-office BP level. This
topic requires further research, given the fact that target organ damage has quite
a high prevalence in RA and is closely related to hypertension
[46].

Conclusions

Physicians involved in the management of RA patients should be alert to the high prevalence
and low awareness of hypertension on the basis of the present robust out-of-office
BP data. They should also take into consideration the facts that specific RA treatment
modalities have effects on the management of arterial hypertension and that the high
prevalence of the WCH phenomenon is associated with increased CVD risk; thus these
patients require close monitoring at the least. Hypertension is definitely a major
contributor to the well-established high CVD risk observed in RA patients. As suggested
by the recent recommendations of the European League Against Rheumatism
[47], hypertension should be placed at the top of the research agenda for the reduction
of CVD risk in RA, and future clinical trials should incorporate out-of-office BP
assessment in their design.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

ADP made substantial contributions to the conception and design of the study, as well
as to the acquisition, analysis and interpretation of the data, and was involved in
drafting the manuscript and revising it critically. DBP made substantial contributions
to the conception and design of the study, acquired data and was involved in revising
the manuscript critically. EZ acquired data and was involved in revising the manuscript.
KA, AAA and GD Konstantonis acquired data and were involved in critically revising
the manuscript. CP made substantial contributions to the conception and design of
the study and was involved in critically revising the manuscript. GD Kitas made substantial
contributions to the conception and design of the study and to the interpretation
of data and was involved in drafting the manuscript and revising it critically. PPS
made substantial contributions to the conception and design of the study and to the
interpretation of data and was involved in drafting the manuscript and revising it
critically. All authors gave their approval of the final version of the manuscript
for publication.